SAN DIEGO – Roger Tsien, a 56-year-old professor of pharmacology at UCSD, won the 2008 Nobel Prize in chemistry early Wednesday for his role in helping develop and expand the use of fluorescent proteins – a widely used and increasingly valuable tool that allows scientists to peer inside living cells or whole animals, watch molecules interact in real-time and ask questions once thought impossible.

He'll share the prize with Osamu Shimomura and Martin Chalfie.

The Nobel Prize in chemistry is one of several being handed out this week by the Royal Swedish Academy of Sciences. It comes with a cash award of roughly $1.4 million, which the researchers will split in equal shares.

Tsien received word of the prize in an early morning phone call. The official ceremony honoring Tsien, Chalfie, Shimomura and the other 2008 Nobel laureates will be held in Stockholm in December.

Shimomura, an 80-year-old Japanese-born organic chemist and professor emeritus at the Marine Biological Laboratory in Woods Hole, Mass., first isolated green fluorescent protein (GFP) in the early 1960s from a jellyfish (Aequorea victoria) found off the west coast of North America, discovering that the protein glowed green under ultraviolet light.

In the 1990s, Chalfie, a 61-year-old molecular biologist at Columbia University in New York City, became the first to show GFP's true value "as a luminous genetic tag" in the laboratory, inserting it into study organisms like Escherichia coli bacteria and Caenorhabditis elegans, a small worm.

Tsien was cited by the Nobel committee for contributing "to our general understanding of how GFP fluoresces" and expanding the utility of fluorescent proteins in science.

The committee said the trios work enables "scientists to follow several different biological processes at the same time," from tracking nerve cell damage caused by Alzheimer's disease to how insulin-producing beta-cells are created in the pancreas of a growing embryo.

“In one spectacular experiment, researchers succeeded in tagging different nerve cells in the brain of a mouse with a kaleidoscope of colors,” the citation said.

Two Americans and a U.S.-based Japanese scientist won the Nobel Prize in chemistry on Wednesday for research on a glowing jellyfish protein that revolutionized the ability to study disease and normal development in living organisms.View the Video

UCSD researcher Roger Y. Tsien talks about sharing the 2008 Nobel Prize in Chemistry for his work on green fluorescent protein (GFP) -- and he thanks the jellyfish it came from for its contribution.View the Video

The Nobel is only the latest, albeit most prestigious, prize to recognize Tsien's work, which colleagues say has dramatically expanded and deepened diverse investigations across multiple fields of science.

“He's the smartest person I know,” said Mark Ellisman, a longtime collaborator and founding director of the National Center for Microscopic Imaging and Research at UCSD. “He's one of those beautiful minds, not only because he thinks deeply about how to fill gaps in what science knows, but also where to look for new questions. He digs deeply, understands quickly and puts the pieces together in ways that create new tools allowing tens of thousands of other scientists to ask new questions.”

Tsien, who comes from a family of scientists and engineers, is more modest. Slender and self-effacing, with close-cropped black hair turning gray and wire-rimmed glasses, he quickly notes that he did not discover fluorescent proteins, nor has he used them to reveal profound biological truths.

“I'm the guy who makes the tools,” he said.

Glow industry

Those tools, however, have arguably changed science. Before the advent of fluorescent proteins, known as FPs, in the early 1990s, biologists and others seeking answers to some of life's mysteries – from basic cellular functions to how neurons stored memories – were often forced to employ disruptive or destructive methods of investigation, from injecting dyes into the cells (which frequently killed them) to actually grinding them up to examine their contents.

In 1992, however, Douglas Prasher at Woods Hole Oceanographic Institute successfully cloned a gene encoding green fluorescent protein, or GFP, from a jellyfish. When exposed to visible light, the protein glowed green. It offered scientists a way to see inside living cells without causing harm.

Chalfie took the next step, proving GFP could function in other organisms.

“One of the wonderful things about fluorescent proteins is they can be made by any modified cell,” said Martin Chalfie, a molecular biologist at Columbia University who first demonstrated the usefulness of GFP as a research tool in the mid-1990s.

“You don't have to add anything to the cell except light. Activate it with light of a certain wavelength and it says, 'Here I am.' You're not really interfering with the cell. Just feeding light in and getting light out.”

Image above depicts a cell dividing into two, using fluorescent probes developed by UCSD's Roger Tsien to indicate different cell structures. The cellular cytoskeleton is orange; the Golgi Apparatus is green; DNA is blue.

+Read Caption

Image above depicts a cell dividing into two, using fluorescent probes developed by UCSD's Roger Tsien to indicate different cell structures. The cellular cytoskeleton is orange; the Golgi Apparatus is green; DNA is blue.

Tsien's contribution was to make this useful but relatively untested tool much, much better.

“He played a seminal role,” said Jennifer Lippincott-Schwartz, head of organelle biology at the National Institute of Child Health and Human Development, part of the National Institutes of Health. “By demonstrating the creative potential of GFP-based reagents and then making them available to the cell biology community, Dr. Tsien has contributed enormously to the direction and progress of cell biology.”

Combining talents in both chemistry and biology, Tsien found ways to make GFP glow more brightly and consistently. He then created a vast, new palette of FP colors: yellow, blue, cyan and orange among them.

In the words of Ellisman, it was “the whole Crayola box.”

“I've always been attracted to colors,” Tsien said. “Color helps makes the work more interesting and endurable. It helps when things aren't going well. If I had been born color-blind, I probably never would have gone into this.”

With many colors to work with, researchers can use FPs to track more than one cellular function at a time. They can tag different proteins-of-interest with different colors, then watch where they go and what they do.

But Tsien didn't stop there. He made FPs even more useful by creating versions that change colors as conditions around them change, such as acidity or calcium levels. For example, if one color-tagged protein interacts with another color-tagged protein, a new color emerges, providing researchers with even more detail and information.

“And,” said Ellisman, “you see it in real-time.”

The importance of GFP and subsequent fluorescent proteins in scientific research cannot be overstated. Before 1992, fewer than half a dozen scientific papers citing GFP were listed on the comprehensive MEDLINE research index.

In the years since, projects and experiments using GFP and other fluorescent proteins have become as ubiquitous as test tubes. Last year alone, according to Zimmer at Connecticut College, more than 12,000 papers were published that used GFP or other FPs.

“I suspect that number will just continue to grow,” Zimmer said. “There are millions of uses for the proteins.”

For example, scientists at the Max Planck Institute for Medical Research in Germany have used proteins developed by Tsien's lab to optically track working neurons in the brain of a live mouse, showing when, where and which neurons were communicating. They described it as “making thought visible.” The method may eventually lead to new ways of identifying the early onset of neurological disorders like Alzheimer's and Parkinson's diseases.

Tsien, who is also a Howard Hughes Medical Institute investigator, has a particular interest in how FPs can be applied to questions in neurobiology and in cancer, a disease that killed his father.

“He had pancreatic cancer. Six months after diagnosis and he was gone. It's not a pretty cancer.”

Varied interests

Tsien's career has been marked by twists and turns. As a boy growing up in Livingston, N.J., he suffered from asthma, which required him to spend long days indoors. So he turned to less physically strenuous pursuits, becoming interested in chemistry. He conducted numerous basement experiments, including one in which a batch of homemade gunpowder inadvertently charred the family ping-pong table.

At the age of 16, he won first prize in the national Westinghouse Science Talent Search for a project that examined how metals bind to organic compounds. He won a National Merit Scholarship, attended Harvard College and graduated at age 20 with a degree in chemistry and physics.

Another scholarship took him to the University of Cambridge in England, but eventually he tired of chemistry. He yearned to do something more dramatic, “dabbling” first in molecular biology, then oceanography.

“I had these romantic dreams of sailing on the blue ocean, but it turned out to be far from that. My research involved measuring oil pollution in a bay. And eventually I realized I didn't really care about things like the height of the Sargasso Sea.”

Instead, he earned a Ph.D in physiology, focusing upon something that seemed endlessly fascinating: the human brain.

Back then, the brain was even more of a black box mystery to researchers. Neuroscience was in its infancy. It was mostly uncharted waters. The work was often inexact, limited and crudely done. To measure electrical activity in the brain, for example, researchers would poke wire electrodes into the brain through holes drilled through patients' skulls. Tsien likened it to “ice fishing,” a blind attempt to catch something interesting.

He thought the brain, which he describes as a kind of “enchanted loom,” a device of myriad and endlessly moving pieces, demanded more sophisticated and less invasive methods of inquiry. He turned back to his roots in chemistry, and when GFP was cloned, he was on his way.

The use of fluorescent proteins is now widespread, both in research laboratories and in pharmaceutical labs designing new drugs. Tsien, however, has mostly moved past FP research, leaving the bulk of it to colleagues and others.

He says he would like to spend his remaining productive research years on the human condition, specifically diseases like cancer, atherosclerosis and stroke. He is currently exploring how FPs might be used to help surgeons better detect and fully excise tumors.

He concedes the research “may not go anywhere. The long history of science is full of stories of researchers successful in one thing failing in another because they got old, lost their edge, wound up wasting time.”

Tsien doesn't think that will happen to him. Though his cancer research is years from human testing and use, it has produced promising results in animal studies.

Throughout his career, Tsien said, he has “never sat long on a topic,” preferring to make some initial discoveries and open new doors for other researchers to follow.

The Nobel Prize, like previous awards, will help him push forward, he said. It may help open new doors, bigger doors.